Pulmonary arterial hypertension is a rare disorder associated with poor survival. Endothelial dysfunction resulting from 1) genetic susceptibility, and 2) a triggering stimulus that initiates pulmonary vascular injury, the two-hit hypothesis, appears to play a central role both in the pathogenesis and progression of PAH. Inflammation appears to drive this dysfunctional endothelial phenotype, propagating cycles of injury and repair in genetically susceptible patients with IPAH and DaPAH. Therapy targeting pulmonary vascular inflammation to interrupt cycles of injury and repair and thereby delay or prevent right ventricular (RV) failure and death have not been tested. Spironolactone, a mineralocorticoid receptor (MR) and androgen receptor antagonist, has been shown to improve endothelial function and reduce inflammation. Current management of patients with severe PAH and NYHA class IV symptoms includes use of MR antagonists for their diuretic and natriuretic effects, late in the course, once clinical right heart failure has developed. Currently, no well described data exists from randomized clinical trials examining the safety and efficacy of MR antagonist therapy in early stages of PAH. In this randomized, double blinded, placebo-controlled spironolactone treatment study, subjects with IPAH and DaPAH undergo 1) standard clinical examinations including 6-minute walk distance and echocardiography; 2) cardiopulmonary exercise testing; 3) plasma profiling of inflammatory markers; 4) gene expression profiling of peripheral blood mononuclear cells (PBMCs); and 5) high-resolution MRI-based determination of pulmonary vascular and RV structure and function. Safety and tolerability of spironolactone in PAH is assessed with periodic monitoring for hyperkalemia and renal insufficiency as well as the incidence of drug discontinuation for untoward effects. We hypothesize that initiating therapy with spironolactone at an earlier stage of disease in subjects with PAH could provide additional benefits through anti-inflammatory effects and improvements in pulmonary artery endothelial function. The concept for the protocol received an NIH Bench-to-Bedside Award in 2011 and a formal protocol was initially approved by the NHLBI IRB in September 2012. Subsequently IRB approval was sought and obtained at collaborating sites and various amendments were brought into alignment at all institutions by summer 2013. In 2013 -15 we established at the NIH a clinical research PAH program consisting of a multidisciplinary medical staff with expertise in cardiology, pulmonary, and critical care as well as a regulatory and research nursing support staff with extensive experience in assuring compliance with clinical protocols while maintaining the highest standards of clinical care. During the 2016-17 reporting period we entered into a collaboration with the Center for Human Immunology (CHI). We will provide CHI with samples that they will process for markers of inflammation, and whole blood gene expression studies in order to expand our ability to immunophenotype subjects with PAH. We also entered into a collaboration with the Laboratory of Transplantation Genomics (LTG) of the NHLBI to do exploratory studies using cell-free DNA based tools to evaluate the pathogenesis of and injury related to PAH. Referrals are currently being received from multiple sites. To date (August 2017) of the 40 pulmonary arterial hypertension subjects enrolled in our Natural History protocol (13-CC-0012) nineteen have been enrolled in this study (Spironolactone Randomized Interventional Trial). This randomized controlled trial is double blinded and open for recruitment. New Recruitment Efforts in the reporting period 2016-2017 include the following: 1) Received approval from the Office of Communications and Media Relations and the NHLBI IRB to develop a web page on the NIH web site highlighting our NIH PAH program. The web page was developed and went live during this reporting period. 2) Coordinating presentations for PH support groups on a continual rotating basis in PA, MD, DC, and VA. During this reporting period attended support groups in Philadelphia, PA; Baltimore, MD; and the District of Columbia. 3) Participated in a meet the expert panel discussion for PH patients at ATS 2017. 4) In collaboration with the Pulmonary Hypertension Association, hosted a symposium entitled Challenges in Pulmonary Arterial Hypertension: Breathing, Beating, and Beyond at the National Library of Medicine on May 19, 2017. Developing for distribution a smaller snapshot index information card describing essential details of the protocol and containing a quick reference bar code to the NIH, CCMD, PAH website.